Design and synthesis of bone-selective osteogenic oxysterol-bisphosphonate analogues

骨选择性成骨氧甾醇二膦酸酯类似物的设计与合成

基本信息

批准号：
9046155
负责人：
Frank Stappenbeck
金额：
$ 49.9万
依托单位：
MAX BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9046155
关键词：
Acids Address Adipocytes Adverse effects Affect Age Agonist Alendronate Allosteric Site American Anabolic Agents Animals Binding Binding Sites Biochemical Biological Biological Assay Blood Circulation Bone Density Bone Formation Stimulation Bone Growth Bone Resorption Cells Cephalic Chemicals Cholesterol Clinical Combined Modality Therapy Cysteine-Rich Domain Defect Development Drug or chemical Tissue Distribution Equilibrium Erinaceidae Evaluation FDA approved Family Forteo Fosamax Fracture Future GTP-Binding Proteins Generations Hormonal Change Human Hydroxycholesterols In Vitro Injection of therapeutic agent Intervention Lead Ligand Binding Mediating Menopause Mesenchymal Stem Cells Methods Minerals Modeling Mus Oryctolagus cuniculus Osteoblasts Osteoclasts Osteogenesis Osteoporosis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Plague Postmenopausal Osteoporosis Process Property Proteins Rattus Reporting Research Risk Safety Site Small Business Innovation Research Grant Structure-Activity Relationship Therapeutic Intervention Tissues Toxic effect Vertebral column Work analog base bisphosphonate bone bone loss bone metabolism cell type clinical investigation cranium cyclopamine design drug mechanism effective intervention extracellular improved in vitro Assay in vitro activity in vivo lifestyle factors lipid biosynthesis mouse model novel older men osteoblast differentiation osteogenic oxidation phase 1 study phase 2 study phase 3 study public health relevance receptor coupling smoothened signaling pathway standard of care success targeted agent therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis directly affects 10 million Americans and another 34 million are osteopenic and at risk for developing osteoporosis. Bisphosphonate drugs, for example alendronic acid (ALN, Fosamax), can improve bone density and reduce fracture risk by slowing osteoclastic bone resorption; however, many of the existing anti-resorptive therapies are plagued with untoward side effects and limited duration of clinical benefits. New and improved strategies for therapeutic intervention in osteoporosis are needed, particularly with new treatments that safely promote anabolic bone growth. A dual therapy approach, addressing both resorption and formation of bone could also be helpful. Presently, there is only one FDA approved bone anabolic agent, Forteo (teriparatide), that confers significant clinical benefits in osteoporosis, but its use is severely restricted due to safety concerns. Multipotent mesenchymal stem cells (MSCs) are precursors of a variety of cell types, including osteoblasts and adipocytes. Formation of new bone is driven by osteoblastic differentiation of MSCs, a process that can be thrown off balance by age, lifestyle factors and hormonal changes that occur with menopause. Parhami et al. discovered that specific oxysterols induce osteogenesis when applied to MSCs while inhibiting their adipogenesis. The most promising proprietary semi-synthetic oxysterol to date, OXY133, displays increased potency for osteogenic differentiation in vitro, including in primary rat, rabbit, and human MSCs, and it stimulates robust localized bone formation in vivo in rat and rabbit spine fusion and crania and femoral defect models. During SBIR Phase I research, we have begun evaluating drug conjugates of osteo- anabolic Oxy133 and Alendronate (ALN), a well-established anti-resorptive drug that also serves as a bone- targeting agent. We have worked out methods for chemical conjugation and characterized biophysical and biological properties of the resulting conjugates. Oxy133-ALN conjugates display strong in vitro binding to bone mineral and stimulate Hedgehog (Hh) pathway signaling and osteogenesis in MSCs. In this application, we propose to further develop Oxy133-ALN conjugates as potential dual therapy agents for osteoporosis, stimulating bone formation by osteoblasts (function of Oxy133), and inhibiting bone resorption by osteoclasts (function of ALN). Expanding on our successful Phase I studies, we propose to perform Phase II studies as part of 3 Specific Aims: Aim 1: Development of scalable methods for the synthesis of Oxy133-ALN conjugates. Aim 2: Evaluation of the inhibition of osteoclastic bone-resorption by Oxy133-ALN conjugates and the possibility of a dual therapy. Aim3: Determination of Oxy133-ALN conjugate tissue distribution properties and evaluation of select Oxy133- ALN conjugates for efficacy in an OVX mouse model.

描述（由申请人提供）：骨质疏松症直接影响 1,000 万美国人，另外 3,400 万美国人患有骨质疏松症，并且有患骨质疏松症的风险。双磷酸盐药物，例如阿仑膦酸（ALN、Fosamax），可以通过减缓破骨细胞速度来提高骨密度并降低骨折风险。骨吸收；然而，许多现有的抗骨吸收疗法都存在不良副作用，且临床获益的持续时间有限。骨质疏松症需要治疗干预，特别是安全促进骨合成代谢生长的新疗法，解决骨吸收和骨形成的双重治疗方法也可能有所帮助，目前 FDA 批准的骨合成代谢药物只有一种：Forteo（特立帕肽）。），这对于骨质疏松症具有显着的临床益处，但由于安全问题，其使用受到严格限制。多能间充质干细胞（MSC）是多种细胞类型的前体，包括成骨细胞和赋予细胞。新骨的形成是由间充质干细胞的成骨细胞分化驱动的，这一过程可能会因年龄、生活方式因素和绝经期发生的激素变化而失去平衡，Parhami 等人发现，当应用于间充质干细胞时，特定的氧甾醇会诱导成骨。迄今为止最有前途的专有半合成氧甾醇 OXY133 在体外（包括在原代大鼠中）显示出增强的成骨分化功效。在 SBIR I 期研究中，我们已经开始评估骨合成代谢 Oxy133 和阿仑膦酸钠 (ALN) 的药物缀合物。，一种成熟的抗再吸收药物，也可用作骨靶向剂。我们已经制定了化学缀合方法，并表征了所得产物的生物物理和生物学特性。 Oxy133-ALN 缀合物在体外表现出与骨矿物质的强烈结合，并刺激 MSC 中的 Hedgehog (Hh) 通路信号传导和成骨作用。在本应用中，我们建议进一步开发 Oxy133-ALN 缀合物作为骨质疏松症的潜在双重治疗剂，刺激骨。成骨细胞形成（Oxy133 的功能），以及破骨细胞抑制骨吸收（ALN 的功能）。研究中，我们建议进行 II 期研究，作为 3 个具体目标的一部分：目标 1：开发 Oxy133-ALN 缀合物合成的可扩展方法；目标 2：评估 Oxy133-ALN 缀合物对破骨细胞骨吸收的抑制作用。双重治疗的可能性目标 3：测定 Oxy133-ALN 缀合物组织分布特性并评估选定的 Oxy133-ALN。结合物在 OVX 小鼠模型中的功效。